1. Field of the Invention
The present invention relates to novel N-2-chlorobenzyl-2-oxo and N-2-chlorobenzyl-2,2-dioxo-1,2,3-oxathiazolidinyl derivatives and their use in the preparation of thieno[3,2-c]pyridine derivatives, particularly ticlopidine.
2. Background Information
Ticlopidine is a compound with desirable blood platelet aggregation inhibition qualities. Previous technology for the preparation of ticlopidine has entailed a low yielding, labor intensive process, employing certain potentially hazardous and expensive materials. The cost of preparing ticlopidine has, therefore, been high. It has been desired to provide improved synthetic process technology that allows for a higher conversion, reduced labor usage, and the elimination of costly, potentially dangerous materials.
A variety of synthetic approaches to making ticlopidine have been described in the art, including improvements on the various steps of such synthetic processes, e.g., as described below.
Ticlopidine was first described by Castaigne in U.S. Pat. No. 4,051,141, where the synthesis thereof was accomplished by condensation of a thieno[3,2-c]pyridine with o-chlorobenzyl chloride.
One desirable method of preparing ticlopidine calls for a N-substituted 2-(2'-thienyl)ethylamine as a key intermediate. The method involved conversion of 2-(2'-thienyl)ethanol to the corresponding sulfonate derivative and then to a secondary amine by reaction with o-chlorobenzylamine and cyclization to give ticlopidine free base, as described by Braye in U.S. Pat. No. 4,127,580.
Previous methods for the preparation of 2-(2'-thienyl)ethylamine have suffered from several disadvantages, including low yields (e.g., where the reactions resulted in mixtures of undesirable side products) and high cost.
For example, Braye, U.S. Pat. No. 4,128,561 describes a two-step process of making 2-(2'-thienyl)ethylamine by converting 2-(2'-thienyl)ethanol to N-2-(2'-thienyl)ethyl phthalimide, and then treating the phthalimide with diethylenetriamine to form the amine. Braye also describes the amination of 2-(2'-thienyl)alkyl sulfonates with ammonia at elevated temperature and pressure. Braye discloses problems encountered in the preparation of primary amines with ammonia, i.e., the tendency for the process to form secondary and tertiary amines as side products.
A process where 2-(2'-thienyl)ethylbromide is treated with alcoholic ammonia at ordinary temperature for 8 days to produce 2-(2'-thienyl)ethylamine is described by Blicke, et al., J. Am. Chem. Soc., 64, 3, 477-480 (1942).
Other synthetic approaches to making 2-(2'-thienyl)-ethylamine have been disclosed in the art, for example, as described below.
The reduction of 2-(2'-thienyl)acetamide with a hydride, e.g., lithium aluminum hydride to form 2-(2'-thienyl)ethylamine is described in Japanese Kokai J6 1221-184-A.
The electrochemical reduction of 2-(2'-nitrovinyl) thiophene to 2-(2'-amino)-2-ethyl-thiophene is described in UK Patent Application GB 2,013,196A.
The catalytic hydrogenation of thienylacetonitrile to form thienyl ethylamines is described in European Patent No. 274,324.
The reduction of 2-(2-nitrovinyl)thiophene to form 2-(2-thienyl)ethylamine employing a boron-containing reducing agent, preferably diborane is described in U.S. Pat. No. 4,906,756.
The reduction of nitrovinyl thiophenes with a hydride, e.g., lithium aluminum hydride to form thiophene ethylamines is described in J. Heterocyclic Chem., 7, 1257-1268 (1970).
The reduction of arylacetonitriles with lithium aluminum hydride/aluminum chloride to form the corresponding 2-aryl-l-aminoethanes is described in Synthesis, 1, 40-42, (1987).
The preparation of thieno[3,2-c]pyridine derivatives, particularly ticlopidine is complicated when the quantities to be prepared are on a large scale. The usefulness of a process for large scale production is gauged by several factors. For example, starting materials have to be available within the purity required; the process must be logistically efficient, e.g., the intermediates should not require isolation or purification (isolation or purification typically result in addition of steps and decrease in yield); and the procedure should return a yield sufficient to make the process commercially feasible. Shortcoming in any of the above parameters result in increased manufacturing costs, which impacts negatively on the desirability of the process. The present invention provides an efficient large scale process for the preparation of thieno[3,2-c]pyridine derivatives, particularly ticlopidine.